Tigecycline (CAS 220620-09-7), (4S,4a5,5aR,12a5)-9-(2-(tert-butylamino)acetamido)-4,7-bis(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,1′-dioxo-2-naphthacenecarboxamide, is the first drug of a new generation of tetracycline antibiotics called glycylcyclines. Tigecycline has a wider range of bioactivity than the parent tetracycline and its analogues discovered so far, and it may be administrated less frequently and/or in lower doses.
Tigecycline has been introduced and marketed by Wyeth under the brand name TYGACIL® and it is especially indicated against acute lethal infections caused by Gram-negative bacteria. TYGACIL® is marketed as lyophilized powder or cake for intravenous injection and the drug substance does not contain excipients or preservatives.
Tigecycline has the following structure:
and was described in U.S. Pat. Nos. 5,494,903 and 5,284,963.U.S. Pat. No. 5,675,030 describes a specific method for obtaining solid Tigecycline by evaporation from a dichloromethane solution. The Tigecycline obtained from this method is amorphous. United States Publication No. 2007/0123497 describes crystalline forms of tigecycline and processes for the preparation thereof.
WO 08/066,935, describes various crystalline forms of tigecycline and processes for the preparation, and which is incorporated herein by reference.
WO 2007/127292, describes crystalline forms I and II of tigecycline, and which is incorporated herein by reference in its entirety.
The present invention relates to the solid state physical properties of tigecycline and processes preparing such tigecycline. These properties can be influenced by controlling the conditions under which tigecycline is obtained in solid form. Solid state physical properties include, for example, the flowability of the milled solid. Flowability affects the ease with which the material is handled during processing into a pharmaceutical product. When particles of the powdered compound do not flow past each other easily, a formulation specialist must necessitate the use of glidants such as colloidal silicon dioxide, talc, starch, or tribasic calcium phosphate.
Another important solid state property of a pharmaceutical compound is its rate of dissolution in aqueous fluid. The rate of dissolution of an active ingredient in a patient's stomach fluid can have therapeutic consequences since it imposes an upper limit on the rate at which an orally-administered active ingredient can reach the patient's bloodstream. The rate of dissolution is also a consideration in formulation syrups, elixirs, and other liquid medicaments. The solid state form of a compound can also affect its behavior on compaction and its storage stability.
These practical physical characteristics are influenced by the conformation and orientation of molecules in the unit cell, which define a particular polymorphic form of a substance. The polymorphic form can give rise to thermal behavior different from that of the amorphous material or another polymorphic form. Thermal behavior is measured in the laboratory by such techniques as capillary melting point, thermogravimetric analysis (“TGA”), and differential scanning calorimetry (“DSC”) and can be used to distinguish some polymorphic forms from others. A particular polymorphic form can also give rise to distinct spectroscopic properties that can be detectable by powder x-ray crystallography, solid state 13C NMR spectrometry, and infrared spectrometry.
Generally, the crystalline solid has improved chemical and physical stability over the amorphous form, and forms with low crystallinity. They can also exhibit improved hygroscopicity, bulk properties, and/or flowability.
The discovery of new polymorphic forms of a pharmaceutically useful compound provides a new opportunity to improve the performance characteristics of a pharmaceutical product. It enlarges the repertoire of materials that a formulation scientist has available for designing, for example, a pharmaceutical dosage form of a drug with a targeted release profile or other desired characteristic. Additionally, new processes for preparing such polymorphic forms of tigecycline may provide more efficient and economical methods, possibly increasing the yield or purity of the polymorphic form obtained. There is a need in the art for processes preparing crystalline Tigecycline and polymorphic forms thereof.